Uric Acid and Cardiovascular Events: A Mendelian Randomization Study

Obesity and diets rich in uric acid-raising components appear to account for the increased prevalence of hyperuricemia in Westernized populations. Prevalence rates of hypertension, diabetes mellitus, CKD, and cardiovascular disease are also increasing. We used Mendelian randomization to examine whet...

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Bibliographic Details
Published in:Journal of the American Society of Nephrology 2015-11, Vol.26 (11), p.2831-2838
Main Authors: Kleber, Marcus E, Delgado, Graciela, Grammer, Tanja B, Silbernagel, Günther, Huang, Jie, Krämer, Bernhard K, Ritz, Eberhard, März, Winfried
Format: Article
Language:English
Subjects:
Aged
Biomarkers - blood
Cardiovascular Diseases - blood
Cardiovascular Diseases - genetics
Clinical Research
Coronary Disease - blood
Cross-Sectional Studies
Female
Follow-Up Studies
Genotype
Humans
Hypertension - blood
Hyperuricemia - blood
Male
Mendelian Randomization Analysis
Middle Aged
Models, Genetic
Multivariate Analysis
Odds Ratio
Oligonucleotide Array Sequence Analysis
Phenotype
Polymorphism, Single Nucleotide
Proportional Hazards Models
Prospective Studies
Regression Analysis
Risk Factors
Uric Acid - blood
Uric Acid - chemistry
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Summary:Obesity and diets rich in uric acid-raising components appear to account for the increased prevalence of hyperuricemia in Westernized populations. Prevalence rates of hypertension, diabetes mellitus, CKD, and cardiovascular disease are also increasing. We used Mendelian randomization to examine whether uric acid is an independent and causal cardiovascular risk factor. Serum uric acid was measured in 3315 patients of the Ludwigshafen Risk and Cardiovascular Health Study. We calculated a weighted genetic risk score (GRS) for uric acid concentration based on eight uric acid-regulating single nucleotide polymorphisms. Causal odds ratios and causal hazard ratios (HRs) were calculated using a two-stage regression estimate with the GRS as the instrumental variable to examine associations with cardiometabolic phenotypes (cross-sectional) and mortality (prospectively) by logistic regression and Cox regression, respectively. Our GRS was not consistently associated with any biochemical marker except for uric acid, arguing against pleiotropy. Uric acid was associated with a range of prevalent diseases, including coronary artery disease. Uric acid and the GRS were both associated with cardiovascular death and sudden cardiac death. In a multivariate model adjusted for factors including medication, causal HRs corresponding to each 1-mg/dl increase in genetically predicted uric acid concentration were significant for cardiovascular death (HR, 1.77; 95% confidence interval, 1.12 to 2.81) and sudden cardiac death (HR, 2.41; 95% confidence interval, 1.16 to 5.00). These results suggest that high uric acid is causally related to adverse cardiovascular outcomes, especially sudden cardiac death.
ISSN:1046-6673
1533-3450
DOI:10.1681/ASN.2014070660